Systematic assessment of prescribed medications and short-term risk of myocardial infarction - a pharmacopeia-wide association study from Norway and Sweden.

Wholesale, unbiased assessment of Scandinavian electronic health-care databases offer a unique opportunity to reveal potentially important undiscovered drug side effects. We examined the short-term risk of acute myocardial infarction (AMI) associated with drugs prescribed in Norway or Sweden. We identified 24,584 and 97,068 AMI patients via the patient- and the cause-of-death registers and linked to prescription databases in Norway (2004-2014) and Sweden (2005-2014), respectively. A case-crossover design was used to compare the drugs dispensed 1-7 days before the date of AMI diagnosis with 15-21 days' time -window for all the drug individually while controlling the receipt of other drugs. A BOLASSO approach was used to select drugs that acutely either increase or decrease the apparent risk of AMI. We found 48 drugs to be associated with AMI in both countries. Some antithrombotics, antibiotics, opioid analgesics, adrenergics, proton-pump inhibitors, nitroglycerin, diazepam, metoclopramide, acetylcysteine were associated with higher risk for AMI; whereas angiotensin-II-antagonists, calcium-channel blockers, angiotensin-converting-enzyme inhibitors, serotonin-specific reuptake inhibitors, allopurinol, mometasone, metformin, simvastatin, levothyroxine were inversely associated. The results were generally robust in different sensitivity analyses. This study confirms previous findings for certain drugs. Based on the known effects or indications, some other associations could be anticipated. However, inverse associations of hydroxocobalamin, levothyroxine and mometasone were unexpected and needs further investigation. This pharmacopeia-wide association study demonstrates the feasibility of a systematic, unbiased approach to pharmacological triggers of AMI and other diseases with acute, identifiable onsets.

Pharmacological advancements in the treatment of chronic anal fissure.

Chronic anal fissure is a tear in the lining of the anal canal that, if not treated appropriately at an early stage, causes considerable anal pain during defaecation. Surgery is no longer considered the first-line treatment of this common condition, as recent advancements in medical treatment has produced promising results in the healing of fissures, thus avoiding the unwanted complications that frequently occur following operative treatment. This review looks at those pharmacological agents used commonly in the treatment of chronic anal fissures and explores alternative therapies that may be of benefit in the future.

Science or fiction: use of nesiritide as a first-line agent?

Nesiritide is an effective agent for the treatment of decompensated CHF. However, the VMAC trial shows that the agent's efficacy and safety are actually more similar than dissimilar to those of nitroglycerin. Indeed, objective reviews have placed nesiritide as a second-line agent behind current standard drug therapy. Finally, nesiritide is approximately 40 times the purchase price of standard agents such as nitroglycerin. For these reasons, we feel that nesiritide should not be considered as first-line therapy. Reflecting this notion, one institution has implemented a protocol that recommends administration of nitroglycerin and intravenous diuretics (using > or = 2 times the usual daily diuretic dose) before using nesiritide. In light of the existing data, we feel that this approach appears to be an appropriate and prudent one for nesiritide's place in therapy.

Assessment of skin safety of a new glyceryl trinitrate transdermal patch. Animal and human studies.

The experimental models and the studies in man employed to assess the skin and general safety of a newly developed glyceryl trinitrate (GTN, CAS 55-63-0) transdermal patch, hereinafter coded EPI, are described. EPI was found well tolerated by the skin after single or 28-day repeated epicutaneous application on the rabbit, devoid of phototoxicity in the mouse, devoid of skin sensitizing potential in the guinea pig and devoid of photosensitizing effects in the guinea pig. Tested were also, with negative results, the cytotoxic, hemolytic and genotoxic potential, the presence of bacterial endotoxins, the systemic and intracutaneous toxicity, and the possible conjunctival irritant effects. The application of EPI for 14 consecutive days on the thoracic skin of 28 healthy volunteers did not provoke subjective discomfort such as itching, burning or pain, or objective skin lesions. On the application site a light and transient erythema was often found demonstrating the transcutaneous absorption of the vasodilating GTN from the patch. The 14-day application was followed after two weeks by the application of a challenge EPI patch to detect a possible skin sensitization by EPI. No skin reaction was elicited, showing that also in man EPI is devoid of skin sensitizing potential. During the 14-day application of EPI several GTN commonly induced systemic adverse reactions were observed, particularly headache, confirming the systemic bioavailability of GTN from the patch. Headache rapidly disappeared after removal of the patch, in parallel with the decrease of the blood concentrations of GTN and of its active metabolites, consistently with the previous pharmacokinetic findings. This is an advantage of the administration of GTN with the transdermal patch because, in the case of unbearable headache, the patient is relieved by the simple removal of the patch.

Rapid development of nitrate tolerance in healthy volunteers: assessment using spectral analysis of short-term blood pressure and heart rate variability.

Nitrate tolerance is characterized by a loss of nitroglycerin (NTG) vasodilating and hypotensive effects during continuous administration, but is difficult to detect clinically. We hypothesized that the decrease in arterial blood pressure (BP) and the reflex sympathetic activation and tachycardia due to baroreflex deactivation associated with rapid intravenous (i.v.) infusion of NTG would be decreased during continuous NTG patch therapy as a result of tolerance to transdermal NTG. Sympathetic activation was measured as the change in amplitude of low-frequency (66-129 mHz) oscillations in BP and heart rate (HR) recorded by a noninvasive method. Eleven healthy male volunteers received rapid i.v. infusion of 0.45 mg NTG in 1 min on 3 consecutive days: before NTG patch, after 22.5 h of patch therapy, and 22.5 h after patch removal. The maximum decrease in systolic BP (SBP) and maximum reflex tachycardia as well as the sympathetic activation produced by i.v. NTG were compared during each of the three study periods. The maximum decrease in SBP was 38 +/- 8 mm Hg before NTG patch and 27 +/- 15 mm Hg during NTG patch (p < 0.05), with return to baseline values (37 +/- 13 mm Hg) after patch removal. There was no significant change in amplitude of reflex tachycardia among study periods. However, low-frequency oscillations in SBP increased by 40 +/- 31% in the absence of NTG patch and by only 9 +/- 35% after 22.5 h of patch therapy (p < 0.05). Patch removal resulted in a significant rebound increase in these oscillations (70 +/- 51%; p < 0.05 vs. baseline).(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of transdermal nitroglycerin therapy with previous long-acting oral or ointment nitrate therapy.

The charts of patients initially treated with long-acting oral or ointment (LAOO) nitrate therapy who subsequently used transdermal nitroglycerin (TNG) patches for the treatment of angina pectoris were reviewed to evaluate patient response, cost-effectiveness, and therapy preference. Fewer hospital admissions and emergency room visits were required during the period of TNG therapy than during the period of LAOO therapy. In addition, more patients reported improvement in angina status during TNG therapy, and a strong patient preference was noted for TNG treatment over the other forms of therapy. The cost analysis showed a trend toward a cost advantage for TNG therapy.

Assessment of dermal glyceryl trinitrate and isosorbide dinitrate for patients with angina pectoris.

Dermal nitrate preparations are claimed to be useful in the treatment of angina, as their slow absorption by-passing the liver leads to a sustained action. Ten patients with angina were exercised on a treadmill after dermal application of 16.64 mg glyceryl trinitrate or 100 mg isosorbide dinitrate or placebo. Exercise duration was significantly increased at one and three hours for both nitrate preparations but not at six hours after application. The calculated workload achieved was significantly increased (p less than 0.01) at one and three hours for both preparations and at six hours (p less than 0.05) for isosorbide dinitrate. Headaches were common with glyceryl trinitrate cream. The dermal nitrate preparations studied had a duration of antianginal action similar to that of oral nitrate tablets. Aside from their value when the oral route cannot be used or absorption may be delayed, dermal nitrate preparations have no advantage over oral preparations for angina pectoris.

Nitrate tolerance and dependence. A critical assessment.

Tolerance and cross-tolerance to nitrates has been known since 1900 but the actual clinical importance of this phenomenon is unclear. Vasodilator treatment of congestive heart failure has provided an important new role for long-acting nitrates. The advent of high-dose nitrate regimens for both angina and heart failure raises the possibility that nitrate tolerance could be a potential detriment to therapy. A number of older studies have documented the development of tolerance and cross-tolerance to blood pressure and heart rate responses to nitrates as well as the rapid onset of tolerance to nitrate headaches in subjects given nitrates on a regular basis. Animal experiments also confirm the ready appearance of nitrate tachyphylaxis. Needleman has proposed a cellular mechanism for nitrate tolerance based on a chemical alteration of nitrate receptors in the vascular wall. In spite of these studies, there is considerable evidence that clinically relevant tolerance to nitrates is rare. Several recent investigations designed to look at this problem using high-dose isosorbide dinitrate (ISD) failed to demonstrate tachyphylaxis to the anti-anginal or hemodynamic effect of ISD. However, very recent work in patients with angina suggests that tolerance to high dose ISD does occur and may reduce the duration of action of long-acting nitrates. Overall, the bulk of current evidence does not support tolerance to be a major problem in nitrate treatment of cardiac diseases, although attenuated vasodilator responses may occur after several weeks of nitrate therapy.